Fedratinib Shows Efficacy in Previously Treated Myelofibrosis, Some Patients With Ruxolitinib Failure

Fedratinib (Inrebic; Bristol Myers Squibb), an oral small-molecule Janus kinase (JAK) inhibitor, demonstrates effectiveness in first and subsequent lines of treatment for patients with myelofibrosis (MF), with particularly meaningful effects observed in patients with low platelet counts and associated thrombocytopenia and those previously treated for their MF, according to authors of a new study published in Blood Cancer Journal.¹

Myelofibrosis patients treated with ruxolitinib can sometimes experience treatment failure or recurrence, necessitating transition to fedratinib. | Image Credit: © digitalpochi | stock.adobe.com

Primarily designed as a JAK2 inhibitor, fedratinib also targets other JAK proteins and displays effects that targets FLT3, blocking inflammatory cytokine production. It has shown efficacy in multiple diseases, including polycythemia vera and MF. Fedratinib ultimately gained FDA approval in 2019 for adults with intermediate-2 or high-risk primary or secondary MF, based on positive results from the JAKARTA (NCT01437787) clinical trial. Patients in that trial achieved reductions in spleen volume and a reduction in myelofibrosis-related symptoms.^2,3

Investigators of new trials sought to investigate fedratinib in other treatment lines, as data in this setting is sparse. In the FREEDOM2 (NCT03952039) trial, fedratinib demonstrated safety and efficacy as a second-line option to reduce spleen size following failure with or intolerance of ruxolitinib (Jakfafi; Incyte Corp) in patients with MF. Given the impacts an additional, effective MF treatment could have on patients, the current investigators sought to review reports from the real-world use of fedratinib to investigate its integration into treatment best practices.^1,4

Beginning with a multicenter Mayo Clinic investigation with fedratinib in 28 patients with MF who were relapsed or refractory to ruxolitinib, the study authors aimed to assess the toxicity, efficacy, and impact of treatment on survival. Among 24 patients who had their spleen response evaluated, only 3 (13%) demonstrated a reduction in spleen size. However, a third of patients experienced at least a 50% reduction in symptom scores, indicating that “fedratinib’s main benefit may lie in providing symptomatic relief,” according to the study authors.¹

Another trial, conducted by Mascarenhas et al, analyzed outcomes of spleen size, MF-specific symptoms, and hematologic responses in the first 6 months of fedratinib treatment. The study collected data from 150 patients across community oncology practices who were previously treated with ruxolitinib. Mean spleen length decreased significantly at 3 and 6 months, while the mean number of symptoms also meaningfully decreased.¹

These results provide evidence for the use of fedratinib in patients who have failed ruxolitinib with intermediate or high-risk MF. Investigators of that study also found that a longer duration of fedratinib led to greater clinical benefits, though the current review authors caution that the study cohort was younger and had a shorter median ruxolitinib exposure (7.6 months) compared to the previously mentioned Mayo Clinic cohort of patients.¹

Recently, the current authors reported on 16 patients with MF on a national managed access program who initiated fedratinib following treatment with ruxolitinib. Overall, after 6 months, 2 patients showed minimal improvements, while 3 patients progressed, and 2 patients showed no change in spleen size. Regarding MF-related symptoms, 43.75% (7) patients reported some improvement, 37.5% (6) had no change, and 18.75% (3) had worsening of their symptoms. Their observations indicated that patients who failed ruxolitinib may have a “modest” response to fedratinib, especially when exposure was greater than 1 year.¹

Ultimately, “identifying patients for whom fedratinib may be the JAK inhibitor of choice is important in an era in which the number of approved JAK inhibitors has increased rapidly and is challenging given the lack of direct between-drug comparisons,” the study authors concluded. Pharmacists and treatment providers play a critical role in observing patients for ruxolitinib failure in the first-line, as a timely identification could enhance the therapeutic potential of fedratinib in that setting.^1,4

REFERENCES

1. Duek A, Leviatan I, Dolberg OJ, and Ellis MH. Fedratinib for the treatment of myelofibrosis: A critical appraisal of clinical trial and “real-world” data. Blood Cancer Journal. 2025;15(6). doi:10.1038/s41408-025-01211-1

2. FDA. FDA approves fedratinib for myelofibrosis. News Release. Released August 16, 2019. Accessed January 22, 2025. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-fedratinib-myelofibrosis

3. ClinicalTrials.gov. Phase III study of SAR302503 in intermediate-2 and high-risk patients with myelofibrosis (JAKARTA). National Library of Medicine. Last Updated January 8, 2016. Accessed January 22, 2025. https://clinicaltrials.gov/study/NCT01437787

4. Gerlach A. Study findings suggest use of fedratinib as treatment in the second line for myelofibrosis. Pharmacy Times. Published October 3, 2024. Accessed January 22, 2025. https://www.pharmacytimes.com/view/study-findings-suggest-use-of-fedratinib-as-treatment-in-the-second-line-for-myelofibrosis